title: Updated genetic score based on 34 confirmed type 2 diabetes Loci is associated with diabetes incidence and regression to normoglycemia in the diabetes prevention program.
abstract: OBJECTIVE
  Over 30 loci have been associated with risk of type 2 diabetes at genome-wide statistical significance. Genetic risk scores (GRSs) developed from these loci predict diabetes in the general population. We tested if a GRS based on an updated list of 34 type 2 diabetes-associated loci predicted progression to diabetes or regression toward normal glucose regulation (NGR) in the Diabetes Prevention Program (DPP).
  
  
  METHODS
  We genotyped 34 type 2 diabetes-associated variants in 2,843 DPP participants at high risk of type 2 diabetes from five ethnic groups representative of the U.S. population, who had been randomized to placebo, metformin, or lifestyle intervention. We built a GRS by weighting each risk allele by its reported effect size on type 2 diabetes risk and summing these values. We tested its ability to predict diabetes incidence or regression to NGR in models adjusted for age, sex, ethnicity, waist circumference, and treatment assignment.
  
  
  RESULTS
  In multivariate-adjusted models, the GRS was significantly associated with increased risk of progression to diabetes (hazard ratio [HR] = 1.02 per risk allele [95% CI 1.00-1.05]; P = 0.03) and a lower probability of regression to NGR (HR = 0.95 per risk allele [95% CI 0.93-0.98]; P < 0.0001). At baseline, a higher GRS was associated with a lower insulinogenic index (P < 0.001), confirming an impairment in β-cell function. We detected no significant interaction between GRS and treatment, but the lifestyle intervention was effective in the highest quartile of GRS (P < 0.0001).
  
  
  CONCLUSIONS
  A high GRS is associated with increased risk of developing diabetes and lower probability of returning to NGR in high-risk individuals, but a lifestyle intervention attenuates this risk.
authors.affiliation: Division of Endocrinology, Department of Medicine, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Hivert
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Jablonski
authors.forename: Leigh
authors.initials: L
authors.lastname: Perreault
authors.forename: Richa
authors.initials: R
authors.lastname: Saxena
authors.forename: Jarred B
authors.initials: JB
authors.lastname: McAteer
authors.forename: Paul W
authors.initials: PW
authors.lastname: Franks
authors.forename: Richard F
authors.initials: RF
authors.lastname: Hamman
authors.forename: Steven E
authors.initials: SE
authors.lastname: Kahn
authors.forename: Steven
authors.initials: S
authors.lastname: Haffner
authors.forename: James B
authors.initials: JB
authors.lastname: Meigs
authors.forename: David
authors.initials: D
authors.lastname: Altshuler
authors.forename: William C
authors.initials: WC
authors.lastname: Knowler
authors.forename: Jose C
authors.initials: JC
authors.lastname: Florez
mesh_terms: D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000235:genetics* / Q000517:prevention & control; D005081:Exercise Therapy; D005838:Genotype; D005951:Glucose Tolerance Test; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D008687:Metformin / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D015431:Weight Loss / Q000502:physiology
chemical_list: D007004:Hypoglycemic Agents; D008687:Metformin